Fc gamma receptors mediate antibody dependent inflammatory response and cytotoxicity as well as certain autoimmune dysfunction. We have determined the crystal structure of a human immunoglobulin receptor, FcgRIIIb, to 1.8 angstrom resolution. The overall fold consists of two immunoglobulin-like domains with an acute interdomain hinge angle of approximately 50 degrees. We now report the crystal structure of a human Fc receptor (FcgRIIIB) in complex with an Fc fragment of human IgG1 determined from an orthorhombic and a hexagonal crystal forms at 3.0 ? and 3.5 ? resolution, respectively. The refined structures from the two crystal forms are nearly identical with no significant discrepancies between the coordinates. Regions of the C-terminal domain of FcgRIII, including the BC, C?E, FG loops, and the C? b-strand, bind asymmetrically to the lower hinge region, residues Leu 234-Pro 238, of both Fc chains creating a 1:1 receptor-ligand stoichiometry. Minor conformational changes are observed in both the receptor and Fc upon complex formation. Hydrophobic residues, hydrogen bonds and salt bridges are distributed throughout the receptor-Fc interface. Sequence comparison of the receptor-ligand interface residues suggests a conserved binding mode common to all members of immunoglobulin-like Fc receptors. Although not in direct contact with the receptor, the carbohydrate attached to the conserved glycosylation residue Asn 297 on Fc may stabilize the conformation of the receptor binding epitope on Fc. An antibody-FcgRIII model suggests two possible ligand induced receptor aggregations. To understand the role of glycosylation in FcR recognition, the receptor affinities of a deglycosylated IgG1 and its Fc fragment were determined by solution binding studies using surface plasmon resonance (SPR). The removal of carbohydrates resulted in a non-detectable receptor binding to the Fc alone and a 15-20 fold reduction of the receptor binding to IgG1, suggesting that the carbohydrates are important in the function of the FcgRIII. Structurally, the carbohydrates attached to Asn 297 fill the cavity between the CH2 domains of Fc functioning equivalent as a hydrophobic core. This may stabilize a favorable lower hinge conformation for the receptor binding. The structure of the complex also revealed the dominance of the lower hinge region in receptor-Fc recognition. To evaluate the potential of designing small molecular ligands to inhibit the receptor function, four lower hinge peptides were investigated for their ability to bind to the receptor FcgRIII. These peptides bind specifically to FcgRIII with affinities 20-100 fold lower than IgG1 and are able to compete with Fc in receptor binding. The results of peptide binding illustrate new ways of designing therapeutic compounds to block Fc receptor activation.